Autonomic nervous system activity is essential for maintaining circulatory and metabolic homeostasis. In order to study sympathetic nervous system function and its relationship to other neuroendocrine systems, it is necessary to measure neurotransmitter, hormonal, and peptide levels in response to various stimuli. The levels of norepinephrine, epinephrine, and dopamine and their metabolites in various body fluids reflect the activity of the neurons from which these neurotransmitters are released. Cerebrospinal fluid levels of monoamine metabolites, enzymes related to neurotransmitter synthesis and degradation, and peptides can be used to assess central nervous system neurotransmitter/neuropeptide function and metabolism. It is necessary to consider the origin of these metabolites to make appropriate corrections for valid interpretation of the data. These strategies have been used to study patients with neurogenic orthostatic hypotension and other disorders in which abnormal adrenergic function is suspected. Intravenous administration of atrial natriuretic peptide (ANP) produces a rapid diuresis and natriuresis in normal subjects. Urine output does not appear to be altered by this peptide in multiple system atrophy (MSA). Lack of responsiveness to ANP could contribute to supine hypertension. Low levels of corticotropin releasing factor (CRF) in CSF from patients with MSA do not correlate with clinical ratings (parkinsonism, depression, dementia) or low levels in CSF of indices for other neurotransmitter systems. Normal CSF peptide levels in pure autonomic failure (PAF) are consistent with peripheral involvement. Sympathetic responses to hypercarbia are diminished in patients with MSA. Post-mortem neurochemical studies of ganglia and spinal cord confirm the pathophysiological distinction between MSA and PAF. Cerebellar excitatory amino acid receptors are altered in MSA, consistent with the known neuropathology of this disorder. Improved diagnostic accuracy and a more - thorough understanding of the underlying mechanisms involved in producing abnormalities of neurotransmitter metabolism and peptide function in these clinical disorders leads to more rational therapeutic approaches.